Intervention: Patients were stratified by center and allocated to an infusion of 25% glucose, 50
U/L of regular insulin, and 80 mEq/L of potassium at 1.5 mL/kg per hour for 24 hours
in addition to usual care (n = 10 091), or usual care alone (n = 10 110).

Outcomes: 30-day all-cause mortality. Secondary outcomes were composite endpoints of death or
nonfatal cardiac arrest, death or cardiogenic shock, and death or reinfarction; and
individual components of the composite endpoints. The study had 99% power to detect
a 20% relative risk reduction in mortality with GIK infusion.

Patient follow-up: 99.85% (intention-to-treat analysis).

Main results

The GIK infusion and usual care groups did not differ for all-cause mortality or for
any secondary outcomes (Table).

Conclusion

In patients with acute myocardial infarction, an infusion of glucose-insulin-potassium
in addition to usual care did not reduce mortality, cardiac arrest, or cardiogenic
shock.

Commentary

In the first GUSTO trial, no benefit was seen from intravenous (IV) heparin compared
with subcutaneous unfractionated heparin in patients receiving streptokinase for ST-elevation
MI (1). Other, much smaller studies have suggested benefit from IV unfractionated heparin
with more fibrin-specific agents, such as acylated plasminogen-streptokinase activator
complex and tissue plasminogen activator, with regard to such surrogate endpoints
as patency. Until now, no megatrial appropriately powered to detect a difference in
mortality has compared an LMWH (or unfractionated heparin) with placebo when administered
with a fibrinolytic agent. The CREATE trial is the first to show that the LMWH reviparin
is superior to placebo in terms of clinical endpoints when administered with any of
several fibrinolytic agents.

The pharmacokinetic properties of several of the LMWHs differ substantially from one
another. Therefore, it is unclear if the demonstrated benefits of reviparin would
be seen with other LMWHs. Reviparin is not available in the United States. Physicians
practicing where it is available ought to administer reviparin over placebo. Whether
reviparin would outperform other LMWHs, or IV unfractionated heparin with fibrin-specific
lytics, remains unknown.

The CREATE trial was a partial factorial design. The other intervention evaluated
was GIK. A remarkable similarity exists between studies of GIK in patients with acute
ST-elevation MI and those examining the effect of magnesium in acute MI. A meta-analysis
of smaller trials of magnesium in acute MI suggested an impressive reduction in mortality
(odds ratio 0.44, 95% CI 0.27 to 0.71) (2). However, the massive fourth International Study of Infarct Survival (ISIS-4) trial
randomized 58 050 patients with acute MI to IV magnesium or no magnesium and
did not show a reduction in 30-day mortality with magnesium therapy. In fact, there
was a trend toward increased mortality with magnesium (P = 0.07) (3).

The GIK story is similar to that of magnesium. A previous meta-analysis of 16 trials
with a total of nearly 5000 acute MI patients showed an 18% mortality reduction with
GIK therapy (4). However, the CREATE-ECLA trial, which enrolled 20 201 patients, failed to
show any benefit with GIK. In the case of magnesium and GIK, the public was lucky.
Neither magnesium nor GIK has been shown to be harmful (except for phlebitis in 3.9%
from IV potassium). (Patients with kidney disease in whom magnesium might be harmful
were excluded from the magnesium trials; those with kidney disease and hyperkalemia
in whom GIK might be harmful were excluded from GIK trials). However, an unknown but
undoubtedly large number of other therapies are routinely administered to patients
on the basis of underpowered randomized trials or even less reliable observational
studies and anecdotal experience. Therefore, perhaps the most important lesson from
CREATE-ECLA is that well designed, appropriately powered trials are needed to confirm
benefit and identify the true risks associated with therapies. When we consider the
recent example of hormone replacement therapy (5), it is quite likely that some therapies currently administered to untold numbers
of patients on a daily basis are not only not beneficial, but are less innocuous than
magnesium and GIK.